1. Field of the Invention
The present invention relates to treatment of mammals by reducing inflammation that triggers the onset of rheumatic diseases, eczema, urticaria, psoriasis, erythema multiforme and lichen planus; inflammation of the gums, and chronic locaized bodily pain derived from acute injury. The present invention is also directed to the treatment of delaying menopause.
2. Reported Developments
Rheumatoid arthritis (hereinafter sometimes referred to as RA) is a common type of arthritis that causes inflammation in the lining of the joints and sometimes other internal organs. RA tends to persist for many years, typically affects many different joints throughout the body, and ultimately can cause damage to cartilage, bones, tendons and ligaments. RA is a chronic, inflammatory, connective-tissue disorder affecting more than five million individuals in the U.S., and accounting for considerable disability in terms of missed work, lost wages, and reduced productivity. The disease can occur at any age, but it most commonly begins in the third to fifth decades of life.
The American College of Rheumotology has established criteria of the diagnosis of rheumatoid arthritis which include:
1. Morning stiffness lasting at least one hour;
2. Swelling of three or more joints;
3. Swelling of the wrist, metacarpophalangeal or proximal interphangeal joints;
4. Symmetric joint swelling;
5. Rheumatoid nodules;
6. Positive rheumatoid factor; and
7. Changes on hand radiographs typical of rheumatoid arthritis that must include erosions or unequivocal bony decalcification.
The correct diagnosis of RA is essential for the clinician and involves certain clinical, laboratory and radiological findings. The diagnosis is influenced by the age and sex of the patient, the pattern of joint involvement, the onset and course of the disease and extrarticular manifestations.
In contrast to rheumatoid arthritis, osteoarthritis (hereinafter sometimes referred to as OA), the illness most often contemplated in the differential diagnosis, usually begins after the age of 50 and affects men and women equally. The joints involved in OA are different from those in RA and are not necessarily symmetrically affected. In OA, joint pathology is primarily mechanical, and synovial membrane inflammation is minimal.
As pertaining to the present invention certain other inflammatory arthritis is differentiated from RA as listed in Table I.
TABLE I ______________________________________ Differential Diagnosis of Rheumatoid Arthritis* ______________________________________ Seronegative spondyloarthropathy (ankylosing spondylitis, reiters syndrome, psoriatic arthritis, enteropathic arthritis) Crystal-induced arthropathy (gout, pseudogout) Diffuse connective tissue disease (systemic lupus erythematosus, polymyosiis, fibromyalgia) Infectious arthritis Osteoarthritis Polymyalgia rheumatica Reactive arthritis Hemoglobinopathies Hemachromatosis Lyme disease Malignancy Thyroid disease Hemophilic arthropathy Hypertrophic osteoarthritis ______________________________________ *Adapted from Textbook of Rheumatology. Philadelphia, W. B. Saunders Co., 1989, pp 943-981
With varying clinical significance, RA can at times affect other areas of the body. The most characteristic of these so-called extra-articular manifestations are rheumatoid nodules. They can be found subcutaneously in up to 25% of rheumatoid patients, especially over extensor surfaces and in pressure areas. Common sites include the olecranon regions, fingers, Achilles tendons, the sacrum and the occiput. The presence of subcutaneous nodules is helpful diagnostically, because they are uncommon in the other forms of inflammatory arthritis. Nodules can also occur in visceral organs, including the lungs and the heart.
As discussed above, the primary cause of RA is unknown. It is thought to be triggered by the presence of an as yet unidentified antigen(s) in an immunogenetically susceptible host, and the nature of the antigen responsible for the arthritic reactions in RA has yet to be clearly established.
Heretofore medical management of RA involved three general approaches.
The first is the use of aspirin and other nonsteroidal anti-inflammatory analgesics, and low-dose glucocorticoids to control the symptoms and signs of the local inflammatory process. These agents are rapidly effective at mitigating symptoms and signs, but they appear to exert little effect on the progression of the disease.
A second group of drugs includes a variety of agents that have been classified as the disease-modifying drugs. These agents appear to have the capacity to decrease elevated levels of acute phase reactants in treated patients, and therefore, are thought to modify the destructive capacity of the disease.
The third class of agents includes the immunosuppressive and cytotoxic drugs that have bee shown to ameliorate the disease process in some patients. These last two classes of agents, however, often cause serious side effects including the development of heart and liver diseases, increase in blood pressure, blindness and malignant neoplasms.
The prior art treatment of RA is based on the following two principles: first, RA is a systemic connective-tissue disorder that is not remediable solely through local measures. Second, RA is a progressive disease that can potentially lead to severe cartilage and bone destruction, organ damage, and decreased life expectancy. Current regimens are predicated on controlling the immune system disturbance to reduce joint discomfort and destruction and this to maintain the patient's activities of daily living.
Available drug preparations for the treatment of RA include the following.
(1) NSAIDS: Nonsteroidal Anti-Inflammatory Drugs
Pharmacologic treatment of RA has advanced steadily in the past several decades, but none of the agents used so far can cure RA. Aspirin remains an important part of the treatment program for many people with RA. To be effective, it must be given in doses much higher than commonly used as an over-the-counter remedy for minor aches and pains. Compared to other similar NSAIDS, aspirin is less expensive and its blood level can be precisely measured. However, it can cause stomach problems in many people. Many physicians recommend the use of enteric (coated) forms of aspirin.
NSAIDS are a large group of drugs that have mechanisms of action similar to aspirin. Like aspirin, these medications can relieve some of the pain associated with RA temporarily. The NSAIDS are the most frequently recommended antirheumatic medications, and the first line of therapy in RA. As a result of the capacity of these agents to block the activity of the enzyme cyclooxygenase and therefore the production of prostaglandins, prostacyclin and thromboxames, they have analgesic, anti-inflammatory and antipyretic properties. Table II lists the most commonly prescribed NSAIDS.
TABLE II ______________________________________ Commonly Prescribed NSAIDS Grouped According To Their Elimination Half-Lives Short Acting Intermediate Acting Long Acting (6 hours) (7 to 14 hours) (15 hours) ______________________________________ Aspirin Diflunisal Azapropazone Diclofenac Naproxen Nabumetone Etodolac Salsalate Oxaprozin Fenoprofen Sulindac Piroxicam Flufenamic acid Flurbiprofen Ibuprofen Indomethacin Ketoprofen Meclofenamic acid Tolmetin ______________________________________
Table III lists the commonly prescribed NSAIDs by classification, half-life and dosage range.
TABLE III ______________________________________ Commonly Prescribed NSAIDS Classification Half Life, hr Dosage Range, mg/day ______________________________________ Proprionic Acid Ibuprofen 2 1200-3200 Naproxen 13 250-1500 Fenoprofen 2 1200-3200 Ketoprofen 1.5 100-300 Oxaprozin 40 600-1800 Phenylacetic Acid Diclofenac 1.5 100-150 Indoleacetic Acid Indomethacin 3-11 50-200 Sulindac 16 300-400 Tolmetin 1-2 600-2000 Fenamate Meclofenamate 2-3 200-400 Oxicam Piroxicam 30-86 20 ______________________________________
These agents are all associated with a wide spectrum of toxic side effects. A common side effect of these drugs is bleeding from the stomach. Overall dose is limited by such gastrointestinal erosions, as well as azotemia, platelet dysfunction, exacerbation of allergic rhinitis and asthma, liver function abnormalities, some renal and cardiovascular irritation, and CNS toxicity like tinnitus, although patients occasionally differ unpredictably in their response to an individual NSAID.
An individual's response to the various NSAIDS is quite variable. Gastrointestinal ulcerations develop in 0 to 30% of NSAID-treated patients. Duodenal lesions are less common than gastric ulcers. The nephrotoxic effects of NSAIDS are well documented. Several mechanisms leading to renal prostaglandin synthesis may adversely affect renal blood flow and in certain situations, lead to acute insufficiency. At high risk are patients with minor or major pre-existing changes in renal function, such as those with changes related to aging, diabetes mellitus, hypertension, congestive heart failure, use of diuretics or low salt diet, cirrhosis, and chronic renal failure of any other cause.
Once the diagnosis of rheumatoid arthritis has been firmly established as an insufficient response to local measures and NSAIDS determined, the addition of DMARDs (disease modifying antirheumatic drugs) to the regimen is normally considered. These drugs include gold compounds, penicillamine, hydroxychloroquine, methotrexate and azathioprine. Estimated rates of efficacy and toxicity of these remittive agents is shown in Table IV.
TABLE IV ______________________________________ Estimated Rates of Efficacy and Toxicity of Remittive Agents EFFICACY EFFICACY TOXICITY High Intermediate ______________________________________ High Cyclophosphamide Azathioprine Parenteral gold Penicillamine Intermediate Methotrexate Auranofin Corticosteroids Sulfasalazine Low Hydroxychloroquine ______________________________________
The ability of these drugs to really modify the disease process is controversial. Unlike NSAIDS or Corticosteroids, their onset of action is gradual over weeks to months. In addition, well-defined toxicity's can occur with these drugs, and clinical laboratory monitoring must be judicious. The response rate to the DMARDs is also variable, and patients may gradually lose their positive benefits over time. They exert minimal direct nonspecific anti-inflammatory or analgesic effects, and therefore, NSAIDS must be continued during their administration, except in a few rare cases when true remissions are induced with them. Remittive agents have a wide spectrum of biological effects, but their exact mechanism of action in PA is unknown. Each is associated with considerable toxicity and there is minimal evidence that disease-modifying drugs actually retard the development of bone erosions or facilitate their healing. A brief description of each drug follows.